The present invention, the discovery of which has been supported by the National Institute of Health, relates to the art of introducing functional groups to an allylic alcohol moiety, and, in particular, to an improved and efficient method for synthesizing compounds requiring stereospecific introduction of functional groups.
Preparation of compounds having not only particular adjunct chemical groups but also regulated structural positioning, has become of great interest in the area of organic synthesis. This is especially true with respect to the intensive research being conducted in antitumor chemotherapy. Limited positive results have been achieved in antitumor research by use of polychemotherapy in which different active substances are associated with known efficacious carrier substituents in a structurally regulated manner.
One of the predominant substituents is an amino sugar moiety. For example, U.S. Pat. Nos. 4,314,999 and 4,216,208 relate to N-acyl derivatives of an amino sugar with an oligopeptide. The antitumor chemotherapeutic activity of such compounds is reported in an article by DeBarbieri entitled "n-Acyl Derivatives of Glucosamine with Oligo-Peptides", Current Chemotherapy, American Society of Microbiology, p. 1183 (April 1978). The amino sugars listed therein as useful in the disclosed chemotherapeutic combination hexosamines, such as glucosamine, galactosamine, or mannosamine.
Other effective antitumor drugs include daunomycin and doxorubicin, which is available as doxorubicin hydrochloride from Adria Laboratories, Inc. under the trade name Adriamycin. Daunomycin consists of the aglycone daunomycinone and the amino sugar, daunosamine. Similarly, doxorubicin consists of the aglycone adriamycinone and daunosamine.
Techiques for synthesizing doxorubicin and daunomycin, and their aglycones, adriamycinone and daunomycinone, are known. See, e.g., Wong, et al., Canadian Journal of Chemistry, Vol. 51, p. 466 (1973); Acton, et al., Journal of Medicinal Chemistry, Vol. 17, No. 6, p. 659 (1974); Kende, et al., Journal of American Chemical Society, Vol. 97, No. 15, p. 4425 (1975) and Vol. 98, No. 7, p. 1967 (1976); and Kende, et al., U.S. Pat. No. 4,021,457. Techniques for attaching daunosamine to the aglycones are also known. See, e.g., Acton, et al., supra, and Smith, et al., Journal of American Chemical Society, Vol. 98, No. 7, p. 1969 (1976). Furthermore, it is well known how to synthesize the aglycones adriamycinone and daunomycinone.
However, while techiques for synthesizing daunosamine are known, the known techniques suffer severe shortcomings that limit their practical utility. For example, the process disclosed in Marsh, et al., Chemical Communications, p. 973 (1967) uses a difficult method to obtain glycal as a starting material and involves the use of a potentially hazardous step of making an azide derivative with sodium azide. Furthermore, in the process disclosed by Marsh, et al., isomers are produced that require separation by a difficult chromatographic step. The process disclosed in Horton, et al., Carbohydrate Research, Vol. 44, p. 227 (1975), requires the use of a number of very expensive reagents and also results in the production of difficult to separate isomers.
U.S. Pat. No. 4,301,276 describes a technique for synthesizing daunosamine hydrochloride and intermediates which can be converted into daunosamine hydrochloride from either L-fucal produced by a rather lengthy synthesis from D-galactose or D-glucose or 6-deoxy-L-idal which also requires a lengthy process. Similarly, U.S. Pat. No. 4,181,795 shows an involved process for synthesizing daunosamine and related compounds, and U.S. patent application Ser. No. 128,298, now U.S. Pat. No. 4,298,726, discloses, inter alia, a process for synthesizing alkyl L-ristosamides and N-benzoyl-L-ristosamine, ristosamine being a configurational analog of daunosamine.
In U.S. Pat. No. 4,024,333 a method of synthesizing daunosamine is shown characterized by conversion of a D-mannose starting material into a 2-deoxy-3-keto intermediate whose oxime is reduced with high stereoselectivity to introduce the correctly oriented D-ribo-3-amino group, followed by a stereospecific step late in the sequence to introduce the terminal C-methyl group with inversion at C-5, to generate the required L-lyxo stereochemistry.
None of the known techniques for the synthesis of the anthracycline antibiotics has been proven to be commercially successful, however, due to difficulties encountered, inter alia, properly oriented hydroxyamination of the amino sugars. By the present invention, however, the above-described problems have been overcome to a significant degree.